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Selective Stalling of Human Translation by Small Molecules

小分子对人类翻译的选择性停滞

基本信息

批准号：
10443568
负责人：
JAMIE H CATE
金额：
$ 29.41万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443568
关键词：
Amino Acid Sequence Amino Acid Substitution Amino Acids Back Behavior Binding Biochemical Biological Assay CRISPR interference Cells Clinic Complex Cryoelectron Microscopy DNA-Protein Interaction Data Development Disease Drug Targeting Effectiveness Escherichia coli Exhibits FRAP1 gene Family Foundations Future G protein coupled receptor kinase Genetic Human Libraries Maps Messenger RNA Modeling Molecular Mutation Nonsense Codon Nucleotides Pathway interactions Peptide Initiation Factors Pharmaceutical Preparations Play Protein Family Proteins Proteome Quality Control RNA, Ribosomal, 23S Reporter Resolution Ribosomal Proteins Ribosomal RNA Ribosomes Role Signal Pathway Structural Models Structure System Technology Testing Therapeutic Translation Initiation Translations Viral Proteins Virus base drug candidate guided inquiry human disease insight interest multicatalytic endopeptidase complex overexpression polypeptide prevent protein complex protein degradation reconstitution ribosome profiling small molecule therapeutic development transcription factor translation to humans

项目摘要

ABSTRACT Protein targets for many human diseases remain “undruggable” due to their underlying biochemical behavior. These limits to discovery of small molecule drugs hold back the promise of developing affordable therapeutics. Here we propose to develop an entirely new mechanism of action that could enable targeting previously “undruggable” proteins, by selectively blocking their translation by the human ribosome. Most drugs and drug candidates known to modulate human translation target translation initiation factor complexes or upstream signaling pathways such as mammalian target of Rapamycin (mTOR). These generally modulate translation of a large number of mRNAs. To date, only one type of compound that selectively targets the ribosome–to induce premature stop codon readthrough–is being evaluated in the clinic. We recently demonstrated that small molecules can selectively stall the translation of human proteins, with very little off-target activity. The compound we analyzed, PF-06446846 (PF846), directly and selectively inhibits the translation of PCSK9 during translation elongation, by stalling the ribosome on the nascent polypeptide residing in the ribosome exit tunnel. However, it remains unclear how this and related compounds selectively stall translation. The few examples of off-target proteins we identified as stalled by PF846 (less than 0.4 percent of the human proteome) exhibit substantial primary structure variability, making it difficult to predict target sequences for future development of selective ribosome-targeting drugs. We have preliminary evidence that PF846 interacts with these diverse nascent chain sequences to induce ribosome stalling by subtly different mechanisms. We propose to elucidate the full molecular mechanism of PF846 stalling of translation, so that this family of compounds can be further optimized to target proteins whose expression or overexpression causes diverse human diseases for which no treatments are now available. This family of compounds could also be optimized to target viruses, which use human translation to synthesize their proteome. These efforts have the potential to open up an entirely new mechanism of action for human therapeutic development.

抽象的许多人类疾病的蛋白质靶点由于其潜在的生化行为而仍然“无法成药”。小分子药物发现的这些限制阻碍了开发负担得起的治疗方法的前景。在这里，我们建议开发一种全新的行动机制，可以实现先前的目标定位 “不可成药”的蛋白质，通过选择性地阻止人类核糖体的翻译。大多数药物和药物已知调节人类翻译目标翻译起始因子复合物或上游的候选者信号通路，例如哺乳动物雷帕霉素靶标 (mTOR)。这些通常调节翻译大量的 mRNA。迄今为止，只有一种类型的化合物能够选择性地靶向核糖体——诱导过早终止密码子通读——正在临床中进行评估。我们最近证明了小分子可以选择性地阻止人类蛋白质的翻译，几乎没有脱靶活性。这我们分析的化合物 PF-06446846 (PF846) 直接选择性地抑制 PCSK9 的翻译在翻译延伸过程中，通过将核糖体停滞在核糖体出口处的新生多肽上隧道。然而，目前尚不清楚该化合物和相关化合物如何选择性地阻止翻译。少数人我们确定被 PF846 阻滞的脱靶蛋白的例子（不到人类蛋白质的 0.4%）蛋白质组）表现出显着的一级结构变异性，使得预测目标序列变得困难选择性核糖体靶向药物的未来发展。我们有初步证据表明 PF846 相互作用利用这些不同的新生链序列通过细微不同的机制诱导核糖体停滞。我们提议阐明 PF846 翻译停滞的完整分子机制，以便该家族化合物可以进一步优化以针对其表达或过度表达导致不同的目标蛋白质目前尚无治疗方法的人类疾病。该化合物家族还可以进行优化以病毒为目标，病毒利用人类翻译来合成蛋白质组。这些努力有可能为人类治疗发展开辟全新的作用机制。